Biomedical subjects

B H Westerink

Publications and source records attributed to B H Westerink.

At least 91 records · Page 5Linked to original sources

PubMed1991

The regulation of dopamine release from nigrostriatal neurons in conscious rats: the role of somatodendritic autoreceptors.

Drugs were infused into the substantia nigra of the rat brain via a microdialysis probe, and the extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid was recorded from a second dialysis probe implanted in the ipsilateral striatum. This approach allowed the evaluation of the sensitivity of nigral autoreceptors to various D1 and D2 agonists and antagonists in conscious animals. Intranigral administration of the specific D2 agonists, quinpirole (LY 171555; 1, 10 and 50 mumol/l) and (-)-N-0437 (10 mumol/l), decreased the output of striatal dopamine, whereas the specific D2 antagonist, (-)-sulpiride (10 and 50 mumol/l), stimulated slightly the release of dopamine from the ipsilateral corpus striatum. Intranigral administration of the D1 agonist, SKF 38393 (100 mumol/l), and the D1 antagonist, SCH 23390 (100 mumol/l), was without effect on the release of striatal dopamine. The results indicate that release-controlling autoreceptors on nerve terminals and autoreceptors controlling impulse flow in the nigra contribute equally to the decrease of striatal DA release caused by a high systemic dose of D2 agonists. The stimulating effect of D2 antagonists on the release of DA is mainly caused by release-controlling autoreceptors localized on nerve terminals. The autoreceptors in the nigra controlling impulse flow contributed somewhat less (about 20%) to this effect. Advantages and disadvantages of the use of a microdialysis probe to deliver drugs to restricted brain areas are discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Importance of the calcium content infused during microdialysis for the effects induced by D2 agonists on the release of dopamine in the striatum of the rat.

Brain microdialysis was used to investigate whether different calcium concentrations (1.2 and 3.4 mmol/l) of the perfusion fluid influenced the effects of D2 agonists on the release of dopamine in the striatum. We used the D2 agonists (-)N-0437 and (+)PHNO. After both local and systemic administration of (-)N-0437 and (+)PHNO, differences were apparent between their effects at 1.2 mmol/l calcium and 3.4 mmol/l calcium Ringer's solution. Although the drugs induced a similar maximal decrease in the release of dopamine with both calcium concentrations, the potency of the effect was significantly greater at 1.2 mmol/l when compared to 3.4 mmol/l calcium Ringer's solution. Thus, when measuring pharmacological effects of dopaminergic agents, it seems essential to use a Ringer's solution containing the physiological calcium concentration in brain microdialysis.

Animals↗

PubMed1991

Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Acute effects of intranigral application of MPP+ on nigral and bilateral striatal release of dopamine simultaneously recorded by microdialysis.

Intracerebral microdialysis in freely moving rats was used to investigate the effects of perfusions with the 1-methyl-4-phenylpyridinium ion (MPP+) in the substantia nigra (SN) on the extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the perfused SN and in the ipsi- and contralateral striata. Following MPP+ perfusion, the release of DA in the SN increased markedly from nondetectable basal levels to about 105 fmoles/min, whereas the output of DOPAC, HVA and 5-HIAA decreased below 25% of basal levels. The intranigral MPP+ application induced, at the same time, an almost immediate, long-lasting decrease in the release of DA in the ipsilateral striatum to less than 20% of basal levels and a moderate increase in the DOPAC and HVA levels, without affecting 5-HIAA output. In the contralateral striatum, the extracellular levels of DA, DOPAC, HVA and 5-HIAA remained unchanged during the entire perfusion experiment. These results suggest that infusion of 10 mM MPP+ into the SN produces an almost immediate blockade of neuronal impulse flow, as shown by the rapid decline in DA release from the ipsilateral striatal nerve terminals. The simultaneously occurring massive increase of the extracellular DA in the SN is, therefore, probably the result of destruction of the nigral cell bodies and/or dendrites following locally applied MPP+. This study clearly illustrates the possibilities of simultaneous microdialysis in various brain areas, allowing pharmacological manipulations on the levels of the cell bodies, while monitoring events in the terminal areas.

1-Methyl-4-phenylpyridinium↗

PubMed1991

Localization of dopamine and its relation to the growth hormone producing cells in the central nervous system of the snail Lymnaea stagnalis.

The distribution of dopamine in the central nervous system of the pond snail Lymnaea stagnalis was investigated by using immunocytochemistry and HPLC measurements. With both methods it was demonstrated that dopamine is predominantly present in the cerebral and pedal ganglia. The dopamine-immunoreactivity was mainly observed in nerve-fibers in the neuropile of the ganglia. Relatively few dopamine-immunopositive cell bodies (diameters 10-30 microns) were found. A large cell in the right pedal ganglion (the so-called RPeD1) stained positively with the dopamine antibody. It has previously been demonstrated that the growth hormone producing cells (GHCs) possess dopamine receptors on their cell bodies. However, dopamine-immunopositive fibers were observed only in the vicinity of the GHC nerve-endings and not close to the GHC cell bodies.

Animals↗

PubMed1991

Effect of precursor loading on the synthesis rate and release of dopamine and serotonin in the striatum: a microdialysis study in conscious rats.

The effects of systemic administration of tyrosine and phenylalanine on the extracellular levels of tyrosine and dopamine were determined by microdialysis in the striatum of awake rats. In addition, the effects of these precursors on in vivo 3,4-dihydroxyphenylalanine (DOPA) formation were determined during continuous infusion of a decarboxylase inhibitor. Both precursors increased the dialysate levels of tyrosine sixfold, but only phenylalanine administration stimulated DOPA formation. However, neither precursor affected the release of dopamine. When the precursor administration was repeated in rats in which the release of dopamine was stimulated by haloperidol pretreatment, again no effect was seen on the release of dopamine. Systemic administration of tryptophan (100 mg/kg, i.p.) during continuous infusion of a decarboxylase inhibitor induced a threefold increase in the formation of 5-hydroxytryptophan and caused an increase in the release of serotonin during infusion of an uptake inhibitor to about 150% of controls. Finally, we investigated whether dietary precursors were able to influence neurotransmitter formation and release. Rats trained to consume their daily food in a period of 2 h were implanted with microdialysis probes. Scheduled eating induced a small increase in the extracellular levels of tyrosine (135% of controls), but the release of dopamine and the formation of 5-hydroxytryptophan during continuous infusion of a decarboxylase inhibitor were not affected.

Animals↗

PubMed1991

Characterization and pharmacological responsiveness of dopamine release recorded by microdialysis in the substantia nigra of conscious rats.

The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5 mumol/L) dissolved in the perfusion fluid. Perfusion of tetrodotoxin (1 mumol/L) produced a virtually complete disappearance of nigral and striatal DA release. Dendritic as well as terminal release of DA was inhibited for several hours when the nerve impulse flow in dopaminergic neurons was blocked by systemic administration of gamma-butyrolactone (750 mg/kg, i.p.). The systemic administration (0.3 mg/kg, i.p.) as well as infusion (1 mumol/L) of the D2 agonist (-)-N-0437 [2-(n-propyl-N-2-thienylethylamino)-5-hydroxytetralin] produced a significant decrease in the release of DA in both the striatum and the SN. DA levels were recorded in the striatum both with and without addition of nomifensine to the perfusion fluid. The decrease in the striatum after (-)-N-0437 was suppressed in the presence of nomifensine. Infusion (1 mumol/L) as well as systemic administration (40 mg/kg) of sulpiride caused a similar increase in the release of striatal DA; this increase was, in both experiments, potentiated by nomifensine coinfusion. Sulpiride administration induced a small increase in the release of nigral DA. Infusion of (-)-N-0437 or (-)-sulpiride into the nigra caused a moderate decrease and increase, respectively, of striatal DA level.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Responsiveness of striatal dopamine release in awake animals after chronic 1-methyl-4-phenylpyridinium ion-induced lesions of the substantia nigra.

Extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid were measured by microdialysis in rat striatum 1 month after a unilateral infusion via a dialysis probe of a high concentration (10 mM) of 1-methyl-4-phenylpyridinium ion (MPP+) into the substantia nigra. The basal extracellular DA concentration at the lesioned side was about 20% of the concentration at the nonlesioned side. However, basal DOPAC dialysate levels from the lesioned striatum represented only 2.4% of those from the contralateral side. Intrastriatal infusion with nomifensine increased the dialysate content of DA about twofold and eightfold at the lesioned and nonlesioned sides, respectively. Co-infusion of nomifensine with (-)-sulpiride caused an additional pronounced rise of the DA output on top of the nomifensine-induced increase at the nonlesioned side, whereas no effect was observed at the lesioned side. Finally, MPP+ (10 mM) was infused for 45 min into both striata. The increase in the dialysate content of DA in response to MPP+ (considered as an index of the total striatal DA content) from the lesioned side was only 0.6% of the MPP(+)-induced DA increase from the nonlesioned side. A strong compensatory response to increased extracellular dopamine was observed in the ipsilateral striatum. This effect was achieved by a severe suppression of reuptake mechanisms, as well as of the autoreceptor feedback response. It is concluded that infusion of MPP+ into the substantia nigra can be used as a chronic biochemical model for clinically manifest parkinsonism.

1-Methyl-4-phenylpyridinium↗

PubMed1990

Microdialysis studies on cortical noradrenaline release: basic characteristics, significance of extracellular calcium and massive post-mortem increase.

Extracellular noradrenaline was measured on-line in the cerebral cortex of the freely moving rat by microdialysis coupled to high performance liquid chromatography and electrochemical detection. High potassium concentrations in the perfusion fluid led to a strong increase, whereas tetrodotoxin led to almost undetectable levels of noradrenaline. This shows that noradrenaline in the dialysate was directly derived from active neuronal release. Noradrenaline levels were sensitive to calcium concentrations in the perfusion fluid: from 10% in calcium-free medium to 200% for 10 mM calcium. An overdose of anesthetic caused a 60-fold increase of noradrenaline post-mortem.

Animals↗

PubMed1990

The effect of acetylcholinesterase inhibition on the release of acetylcholine from the striatum in vivo: interaction with autoreceptor responses.

The release of acetylcholine from the rat striatum is under inhibitory control of muscarinic autoreceptors. Since in vivo release studies are generally performed in the presence of an acetylcholinesterase inhibitor, modifications of responses to muscarinic receptor agonists and antagonists may be expected. In this study we show that the addition of 0.1 microM neostigmine bromide to the perfusion Ringer in a dialysis experiment attenuates the responses obtained by infusion of 100 microM oxotremorine and potentiates the effect of infusion of 1 microM atropine. Furthermore it is shown that under physiological conditions the muscarinic autoreceptors are not fully occupied, since infusion of 1 microM atropine did not affect the release of acetylcholine when no acetylcholinesterase inhibitor was added to the perfusion Ringer.

Acetylcholine↗

PubMed1990

Effect of choline administration on the release of acetylcholine from the striatum as determined by microdialysis in awake rats.

The release of acetylcholine from the striatum was recorded by an on-line microdialysis method during intraperitoneal administration of high doses of choline (1 mmol/kg). The effect of choline administration was also studied in rats in which the striatal release of acetylcholine was stimulated by atropine infusion. The results did not support the idea that the release of acetylcholine in the striatum is under the control of precursor availability.

Acetylcholine↗

PubMed1990

An M3-like muscarinic autoreceptor regulates the in vivo release of acetylcholine in rat striatum.

Selective muscarinic antagonists were used in an attempt to characterize the muscarinic autoreceptor modulating the release of acetylcholine in the striatum of the rat. In vivo microdialysis was applied to infuse atropine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine), pirenzepine or AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro[2,3-b][1,4]benzodiazepine-6-one), leading to a dose-dependent increase in the overflow of acetylcholine, the order of potency being: atropine greater than 4-DAMP greater than pirenzepine greater than AF-DX 116. We conclude from these data that the muscarinic receptor modulating release in the striatum is of the M3 type.

Acetylcholine↗

PubMed1990

Dopaminergic regulation of striatal cholinergic interneurons: an in vivo microdialysis study.

In vivo microdialysis was used to study the putative inhibitory effects of dopamine on cholinergic interneurons in the striatum of conscious rats. The dopamine receptor agonists apomorphine (0.3 and 3 mg/kg, s.c.) and (+/-)N-0437 (1.4 mg/kg, s.c. decreased interstitial concentrations of acetylcholine while increasing those of choline. In contrast, the dopamine receptor antagonists haloperidol (0.1 and 1 mg/kg, i.p.) and (+/-)sulpiride (20 mg/kg, i.p.) enhanced striatal acetylcholine output but had little effect on choline. Previously, a lack of effect of these drugs on striatal acetylcholine was reported. The main methodological difference between these studies was that the calcium concentration of the microdialysis perfusion solution was 3.4 mM in the former study versus 1.2 mM in the present experiments. The results of this study reemphasize the importance of the calcium concentration in determining the effects of drugs on central neurotransmitter release, and confirm a role of dopamine in the regulation of striatal cholinergic interneurons.

Acetylcholine↗

PubMed1990

Dopaminergic-cholinergic interactions in the striatum: the critical significance of calcium concentrations in brain microdialysis.

Brain microdialysis experiments were performed to assess the effects of calcium (1.2 mmol/l and 3.4 mmol/l) in the perfusion solution on a variety of pharmacological treatments known to affect the release of dopamine (DA) and/or acetylcholine (ACh). Intrastriatal infusion of the muscarinic receptor agonist oxotremorine (100 microM), the selective dopamine D-2 receptor agonist (-)-N-0437 (1 microM), and the indirect DA agonists (+)amphetamine (10 microM) and nomifensine (1 microM) via the dialysis probe did not affect the overflow of ACh when the perfusion fluid contained 3.4 mmol/l calcium. In contrast, these compounds produced pronounced decreases in the overflow of ACh at 1.2 mmol/l calcium. Intrastriatal infusion of the muscarinic receptor antagonist atropine (1 microM) increased the output of ACh both at 1.2 mmol/l and 3.4 mmol/l calcium. The selective DA D-2 receptor antagonist (-)-sulpiride (1 microM) did not affect the overflow of ACh at either calcium concentration. Infusion of oxotremorine and atropine had no effect on the overflow of DA at either 1.2 mmol/l at 3.4 mmol/l calcium. (-)-N-0437 decreased and (-)-sulpiride increased DA overflow, both effects being independent of the calcium concentration in the perfusion fluid. Nomifensine and (+)amphetamine caused relatively (but not absolutely) larger increases in the overflow of DA at 1.2 mmol/l calcium. These findings emphasize the critical importance of the calcium concentration of the perfusion fluid in determining the nature of pharmacological responses in microdialysis experiments, and demonstrate that locally applied dopaminergic drugs can modulate striatal cholinergic function.

Acetylcholine↗

PubMed1990

Characterization of the in vivo release of dopamine as recorded by different types of intracerebral microdialysis probes.

Microdialysis of dopamine was performed in the striatum with four different microdialysis cannulas: a trans-cerebral probe, a U-shaped probe, a I-shaped probe and a commercially available I-shaped probe (Carnegie). The commercial cannula was studied with as well as without a guide cannula. The effect of infusion of tetrodotoxin (TTX) or calcium free-Ringer solution on the dialysate content of dopamine released was determined 2 h after implantation (day 1) as well as 24 h after implantation (day 2). Two hours after implantation, all cannulas displayed a certain amount of TTX-independent overflow of dopamine. The best results were obtained with the I-shaped cannula: already 2 h after implantation of the probe, about 85% of the release of dopamine was TTX-dependent. In case of the trans-cerebral cannula and the Carnegie cannula (implanted without guide in anesthetized rats), 70-75% of the output of dopamine was TTX-dependent. When the Carnegie cannula was implanted with a guide cannula, only 45% of the dopamine output was TTX-dependent. The responses to calcium-free perfusion were much more variable. Dopamine output in I-shaped and the U-shaped probes was virtually insensitive to calcium-free perfusion in acute experiments. Twenty-four hours after implantation of the probes, the calcium- and TTX-dependency was much more pronounced. All types of cannulas studied now sampled dopamine that was completely TTX-dependent. Calcium-free perfusion caused a reproducible disappearance of dopamine from the dialysates to 30% of controls, in all cannulas studied. When the removable Carnegie cannula was re-implanted 24 h after its first implantation, 91% of the dopamine overflow was TTX-sensitive. These results confirm earlier conclusions that microdialysis experiments should be carried out at least 24 h after implantation of the probe.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Effects of D-2 agonists on the release of dopamine: localization of the mechanism of action.

Brain microdialysis was used to localize the mechanism of action of the effect induced by the D-2 agonists (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin [(-)-N-0437] and (+)-4-propyl-9-hydroxynaphtoxazine [(+)-PHNO], on the release of DA in the striatum. Both agonists induced a stronger decrease in the release of DA when administered systemically in comparison to local administration. This suggests that the action of D-2 agonists is not exclusively mediated by autoreceptors regulating the release of DA at the level of the nerve terminals. By co-infusing nomifensine (10 microM) the effect of intrastriatally administered D-2 agonists on the release of DA could be completely abolished. As both agonists were effective when administered systemically in normal rats and in rats with kainic acid lesions performed in the striatum during nomifensine infusion, the effects induced by D-2 agonists seem to be partly mediated by autoreceptors situated on cell bodies, regulating the impulse flow of the neuron. In addition, D-2 receptors located on postsynaptic structures participating in the striatonigral feedback loops were suggested to be involved. (-)-N-0437 and (+)-PHNO were less effective after systemic administration when kainic acid lesioned rats were used in comparison with normal rats. Thus, D-2 agonists interact in a complex way with D-2 receptors for displaying their effect on the release of DA: autoreceptors situated on nerve terminals and on cell bodies as well as D-2 receptors located on postsynaptic structures participating in the striatonigral neuronal loops may all be involved to a certain extent in the mechanism of action of D-2 agonists.

Animals↗

PubMed1990

Dopamine-acetylcholine interaction in the striatum studied by microdialysis in the awake rat: some methodological aspects.

In order to evaluate the dopamine/acetylcholine balance hypothesis, sulpiride, (-)-N-0437, oxotremorine or physostigmine were administered intraperitoneally to rats, whereas the extracellular levels of acetylcholine and dopamine in the striatum were recorded by microdialysis. The changes in dialysate concentration of the transmitters did not support the supposed interaction between dopaminergic and cholinergic neurons. Next, we infused direct and indirect dopamine agonists such as (-)-N-0437, amphetamine and nomifensine via the dialysis membrane. The dopamine agonists had no effect on the release of acetylcholine when the calcium concentration of the perfusion fluid was 3.4 mmol/l, but the agonists effectively inhibited the release of the transmitter when the calcium concentration was 1.2 mmol/l. The cholinergic drugs physostigmine, oxotremorine, atropine did not affect the release of dopamine.

Acetylcholine↗

PubMed1990

Use of microdialysis for monitoring tyrosine hydroxylase activity in the brain of conscious rats.

An on-line microdialysis system was developed which monitored the 3,4-dihydroxyphenylalanine (DOPA) formation in the striatum during infusion of a submicromolar concentration of an L-aromatic amino-acid decarboxylase inhibitor (NSD 1015). The absence of DOPA in dialysates of 6-hydroxydopamine-pretreated rats and the disappearance of DOPA after administration of alpha-methyl-p-tyrosine indicated that the dialyzed DOPA was derived from dopaminergic nerve terminals. Next we investigated whether the steady-state DOPA concentration in striatal dialysates could be considered as an index of tyrosine hydroxylase activity. The increase in DOPA output after intraperitoneal administration of haloperidol or gamma-butyrolactone and the decrease in DOPA output after intraperitoneal administration of apomorphine are in excellent agreement with results of postmortem studies, in which a decarboxylase inhibitor was used to measure the activity of tyrosine hydroxylase. The effect of haloperidol on DOPA formation was not visible when a U-shaped cannula (0.80 mm o.d.) was used. Some methodological problems related to microdialysis of the haloperidol-induced increase in DOPA formation are discussed. We concluded that the proposed model is a powerful and reliable in vivo method to monitor tyrosine hydroxylase activity in the brain. The method is of special interest for investigating the effect of compounds which are not able to pass the blood-brain barrier. As an application of the method in the latter situation, we report the effect of infusion the neurotoxin 1-methyl-4-phenylpyridinium ion (10 mmol/L infused over 20 min) on the activity of striatal tyrosine hydroxylase.

1-Methyl-4-phenylpyridinium↗